TBK1 Is a Synthetic Lethal Target in Cancer with VHL Loss
Abstract
TANK binding kinase 1 (TBK1) is an important kinase involved in the innate immune response. Here we discover that TBK1 is hyperactivated by von Hippel-Lindau (VHL) loss or hypoxia in cancer cells. Tumors from patients with kidney cancer with VHL loss display elevated TBK1 phosphorylation. Loss of TBK1 via genetic ablation, pharmacologic inhibition, or a new cereblon-based proteolysis targeting chimera specifically inhibits VHL-deficient kidney cancer cell growth, while leaving VHL wild-type cells intact. TBK1 depletion also significantly blunts kidney tumorigenesis in an orthotopic xenograft model in vivo. Mechanistically, TBK1 hydroxylation on Proline 48 triggers VHL as well as the phosphatase PPM1B binding that leads to decreased TBK1 phosphorylation. We identify that TBK1 phosphorylates p62/SQSTM1 on Ser366, which is essential for p62 stability and kidney cancer cell proliferation. Our results establish that TBK1, distinct from its role in innate immune signaling, is a synthetic lethal target in cancer with VHL loss.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 01, 2020
- Source ID
- 10.1158/2159-8290.cd-19-0837
Entities
People
- Albert S Baldwin
- Chengheng Liao
- Emily M. Wilkerson
- Frances Potjewyd
- Haibiao Xie
- Johnny Castillo Cabrera
- Kai Hong
- Kan Gong
- Laura E Herring
- Lianxin Hu
- Lindsey I James
- Ling Xie
- Qing Zhang
- Xian Chen
- Xianming Tan
- Xijuan Liu
Organizations
- American Cancer Society
- Cancer Prevention and Research Institute of Texas
- Huazhong University of Science and Technology
- National Cancer Institute
- Peking University
- United States Department of Defense
- University of North Carolina
- University of Texas at Austin